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Age and cumulative glucocorticoid exposure are key risk factors for low bone mineral density in systemic lupus erythematosus.
Low bone mineral density and osteoporosis are well-known comorbidities with systemic lupus erythematosus. Now, new research finds that age and cumulative glucocorticoid exposure are key risk factors in a group of Canadian patients.
The research found a prevalence of low bone mineral density in 31.5 percent of patients in the inception members of the Toronto Lupus Cohort. Unsurprisingly, older age and greater cumulative exposure to glucocorticoids predicted bone mineral density abnormalities, but the problem was quite serious even in young patients and men, who aren't typically at as high of risk of low bone density or osteoporosis as women, the researchers found.
"We found that the patients who had low bone density, they were only 5.9 years from the diagnosis of lupus, with a mean age roughly 48 years," said study researcher Zahi Touma, M.D., Ph.D, a rheumatologist at the University of Toronto. "It's really an important issue, and that's why we should be checking for bone density early in disease."
Research on low bone density, osteoporosis and lupus has shown clearly that bone comorbidities are common with lupus. The precise prevalence of the problem, however, is not very clear. One 1993 study published in the journal Arthritis and Rheumatology found a prevalence of osteopenia of 25 percent in a group of 46 patients with systemic lupus erythematosus. A 2005 study in the journal Lupus looked at a group of postmenopausal Chinese women with lupus and found that 74 percent qualified as osteopenic using measurements at the femoral neck. Similarly broad ranges are found in assessments of osteoporosis. On the low end, a 2003 study in The Journal of Rheumatology found a prevalence of osteoporosis of 1.4 percent in premenopausal women with lupus, lower than age- and sex-matched Caucasians. On the high end, a 2003 Clinical Rheumatology study found that 68.7 percent of SLE patients treated with glucocorticoids had osteoporosis at at least one site.
Sample size and characteristics can explain some of the variance between studies: postmenopausal patient samples are likely to differ from premenopausal samples, for example. Some studies look at inception cohorts, in which patients are enrolled within a year of diagnosis, and some look at cohorts that include patients who may have been diagnosed decades ago. Different researchers have also used different cut-offs and scoring systems, Dr. Touma said, with most focusing on T scores, or the standard deviation difference in bone density from a healthy adult of the same sex. Dr. Touma and his colleagues calculated both T scores and Z scores, which take into account age, sex, weight, ethnicity and race.
The Consequences of Bone Loss
Whatever the prevalence, the bone loss in lupus patients has serious consequences. Various studies have found between a 1.8-fold and a 4.7-fold increased risk of fractures in women with systemic lupus erythematosus versus healthy controls, he said.
Dr. Touma and his colleagues used the Canadian Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis. For premenopausal women and men under the age of 50, a score of less than or equal to 2 standard deviations below normal indicated low bone mineral density. For postmenopausal women and men over 50, a T score of more than 2.5 standard deviations below the norm indicated osteoporosis, while a T score of less than 2.5 but more than 1 standard deviation indicated low bone mineral density. These number are similar to international recommendations. The International Society for Clinical Densitometry recommends using Z-scores in adults under the age of 50 and marks the cutoff for low bone density at 2 standard deviations below the norm for age, sex and race or ethnicity. The World Health Organization T-score cutoffs are identical to those used in the Canadian guidelines.
Two hundred and eighty-six patients out of the 1,807-member Toronto Lupus Cohort had at least one bone mineral density measurement at the time of the study. These 286 patients were evaluated for disease severity using SLEDAI. Demographic information and treatment information was also collected.
The researchers found an overall prevalence of 31.5 percent, combining both osteoporosis and low bone mineral density. Seventeen percent of premenopausal women had low bone mineral density, as did 27 percent of men under the age of 50. In post-menopausal women, 43 percent had low bone mineral density and 12.3 percent had osteoporosis. Among men over 50, 80 percent had low bone mineral density, and 10 percent had osteoporosis.
"The sample size here is very small, so we have to be careful how to interpret the results [in the older men]," Dr. Touma said. There were only 10 men over 50 in the study, and only 22 under the age of 50. Nevertheless the findings highlight the fact that no lupus patient is immune to bone loss. There is some research suggesting that men with lupus present with more severe disease, he said, so male patients might be exposed to higher doses of glucocorticoids than women, putting them at risk of bone loss.
"We should be careful with bone density assessment in lupus male patients as well," he said.
The researchers also found that 11.1 percent of the entire inception cohort (769 people) had experienced peripheral or vertebral fragility fractures, with peripheral fractures being the most common at 5.7 percent of all breaks. Of the patients with a bone mineral density assessment, 7 percent had experienced fractures, and half of those had an abnormal bone mineral density at their first test. Seventy percent had been treated with bisphosphonates within two years of that test.
Older age and greater cumulative exposure to glucocorticoids predicted low bone mineral density and osteoporosis after a multivariate analysis, Dr. Touma and his colleagues found. They reported their findings in the journal Lupus in August.
The Connection Between Disease Activity and Bone Loss
The researchers found no indication that disease activity was linked with bone loss, though that could be a consequence of the sample size or study demographics. Some studies fail to find a link between disease activity and bone and others do. A 2011 review in Arthritis Care & Research noted studies linking complement C4 levels and low lumbar spine bone mineral density, as well as organ damage and reduced bone mineral density. Inflammation may increase osteoclastic bone resorption and reduce osteoblastic bone formation, the researchers wrote in that review. High TNF and oxidized low-density lipoprotein levels observed in active disease could increase osteoclast activity and hasten bone loss.
Glucocorticoids are known to contribute to low bone density, but might also counteract any negative impacts of inflammation. Cross-sectional studies show conflicting results, according to the 2011 review, and very few longitudinal studies have been conducted. Those that have been done follow patients for only short periods. The 2003 Clinical Rheumatology study that found high rates of osteoporosis was one; it found increased bone loss in the hip and lumbar spine in patients who had taken glucocorticoids versus those that were glucocorticoid-naÃ¯ve.
A quality indicator set for systemic lupus erythematosus including guidelines for osteoporosis was released in 2009; those guidelines recommend bone mineral density testing, supplemental calcium and vitamin D for patients treated with more than 7.5 milligrams a day of prednisone or equivalent for more than three months. Treatment with an anti-resorptive or anabolic agent is recommended for patients who have received 7.5 milligrams a day of prednisone for more than a month and who have a fracture history or T scores indicating bone loss. The American College of Rheumatology further recommends additional vertebral fracture assessment. The 2011 review ends with a suggestion that lupus patients who haven't been treated with glucocorticoids but who do have additional osteoporosis risk factors should be screened.
Dr. Touma argues that expanding bone density testing is crucial. "Getting a baseline bone density is very important when you see the patient early in the course of the disease," he said. Questions remain, however, about how to stratify risk factors and protective factors for bone loss in lupus patients. He and his colleagues plan to conduct longitudinal research with their Toronto cohort to study the change in bone density over time.
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